Abstract
Aims: p53 is known to induce apoptotic and necrotic cell death in response to stress, although the mechanism of these pathways is unknown. The aim of this study was to determine the molecular mechanism that determines p53's decision to select the apoptotic or necrotic mode of cell death. Results: Gold nanoparticles (Au-NPs) induced both apoptosis and necrosis in cancer cells in a p53-dependent manner. In cells undergoing apoptosis and necrosis, differential patterns of reactive oxygen species (ROS) generation were observed that leads to the activation of two different sets of p53-interacting kinases and acetylases. The differential activation of cellular kinases and acetylases caused dissimilar patterns of p53 phosphorylation and acetylation. In apoptotic cells, p53 was post-translationally modified in the core-domain, whereas in necrotic cells, it was modified at both N-and C-terminii, thus displaying differential DNA-binding activity. Au-NP10 and Au-NP80 activated fifty apoptotic and fifty nine necrotic p53-downstream genes, respectively. Both Au-NP10 and Au-NP80 showed HCT (p53 ++) tumor regression in mice xenografts. Innovation: This study established for the first time that, in cancer cells, Au-NP-mediated apoptosis and necrosis are controlled by differential activation of p53 and its downstream genes. Further, both Au-NP10 and Au-NP80 were shown to regress HCT (p53 ++) tumors via apoptotic and necrotic pathways, respectively. Conclusion: Au-NP-mediated p53 activation at both transcription and proteome level, through ROS-mediated p53 post-translational modification pattern, is responsible for tumor regression, which may further find wider application of nanoparticles in cancer therapy.